| Autor: |
Cao K; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Luo K; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Zheng Y; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Xue L; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Huo W; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Ruan P; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Wang Y; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Xue Y; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Yao X; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Xia D; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn., Gao X; Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn. |
| Abstrakt: |
Microtubules are highly dynamic structures, and their dynamic instability is indispensable for not only cell growth and movement, but also stress responses, such as endoplasmic reticulum (ER) stress. Docetaxel, a microtubule targeting agent (MTA), is the first-line drug for cancer treatment by simultaneously promoting microtubule dysregulation- and ER stress-induced cell death. However, it also causes adverse effects and drug resistance, especially in triple-negative breast cancer (TNBC) with a poor prognosis and high mortality rate. In this study, we developed a peptide-templated gold nanocluster, namely GA. GA significantly sensitizes TNBC cells to docetaxel, causing severe cell death. This effect is further validated by a 3D tumor spheroid model. Mechanistically, GA disrupted microtubule dynamic instability, meanwhile promoting PERK-mediated ER stress. Interestingly, ER stress inhibitors profoundly suppressed microtubule dysregulation, suggesting a retrograde regulation of ER stress on microtubules. In vivo , the combined administration of docetaxel and GA significantly suppresses tumor growth while docetaxel alone cannot. GA similarly elevated the level of caspases and PERK within tumors as in vitro . Importantly, GA treatment also profoundly promoted the production of anti-tumor inflammatory cytokines. Collectively, we developed an ER-microtubule regulatory nanomaterial that enhanced the therapeutic effect of docetaxel by elevating tumor cell death and anti-tumor cytokine production, providing a potential supplemental strategy for TNBC treatment. |
